A bagging approach for improved predictive accuracy of intradialytic hypotension during hemodialysis treatment.

The primary objective of this study is to enhance the prediction accuracy of intradialytic hypotension in patients undergoing hemodialysis. A significant challenge in this context arises from the nature of the data derived from the monitoring devices and exhibits an extreme class imbalance problem. Traditional predictive models often display a bias towards the majority class, compromising the accuracy of minority class predictions. Therefore, we introduce a method called UnderXGBoost. This novel methodology combines the under-sampling, bagging, and XGBoost techniques to balance the dataset and improve predictive accuracy for the minority class. This method is characterized by its straightforward implementation and training efficiency. Empirical validation in a real-world dataset confirms the superior performance of UnderXGBoost compared to existing models in predicting intradialytic hypotension. Furthermore, our approach demonstrates versatility, allowing XGBoost to be substituted with other classifiers and still producing promising results. Sensitivity analysis was performed to assess the model's robustness, reinforce its reliability, and indicate its applicability to a broader range of medical scenarios facing similar challenges of data imbalance. Our model aims to enable medical professionals to provide preemptive treatments more effectively, thereby improving patient care and prognosis. This study contributes a novel and effective solution to a critical issue in medical prediction, thus broadening the application spectrum of predictive modeling in the healthcare domain.

miR-146a participates in the regulation of cancer stemness of oral carcinoma cells.

Background/purpose: Increasing evidence regarded the existence of cancer stem cells (CSCs) as a leading cause of therapy failure and tumor relapse due to their self-renewal and differentiation abilities. Although ectopic overexpression of micro-RNAs (miRNAs) can modulate the cancer stemness and tumor development in oral cancer, their molecular mechanism is still unclear. Therefore, in the present study, we attempt to uncover the role of miR-146a in the maintenance of oral CSCs. Materials and methods: The expression of miR-146a was determined using qRT-PCR analysis. Aldehyde dehydrogenase (ALDH) enzymic activity and sphere formation assays were used to evaluate the cancer stemness and self-renewal, respectively. Functional assays, including migration/invasion Transwell and colony formation assay, were used to evaluate the aggressive abilities. Luciferase reporter assay was performed to validate the relationship between miR-146a and Numb. Results: In the present study, we reported an increased expression of miR-146a in the oral squamous cell carcinoma (OSCC) specimen, primary OSCC cells sphere, and high ALDH1 activity population within OSCC cells. Inhibition of miR-146a significantly suppressed the ALDH1 activity, self-renewal capacity, and aggressive abilities, including migration, invasion, and colony formation. Moreover, we demonstrated that Numb is a functional target of miR-146a in OSCC-CSCs. Notably, silencing of Numb could retrieve the self-renewal and migration impaired by knockdown of miR-146a. Conclusion: Our results indicate that miR-146a can regulate the cancer stemness in OSCC by modulating Numb, and hence miR-146a/Numb axis can serve as a potential target for oral cancer therapy.

α-Mangostin Inhibits the Activation of Myofibroblasts via Downregulation of Linc-ROR-Mediated TGFB1/Smad Signaling.

Oral submucous fibrosis (OSF) is a premalignant disorder and persistent activation of myofibroblasts is implicated in this pathological progression. Increasing attention has been addressed towards non-coding RNA-regulated myofibroblasts activities and the effects of phytochemicals on non-coding RNA modulation are of great importance. In the present study, we examined the anti-fibrosis property of α-mangostin, a xanthone isolated from the pericarp of mangosteen. We found that α-mangostin exhibited inhibitory potency in myofibroblast activities and expression of fibrosis markers at the concentrations that caused neglectable damage to normal cells. Apart from the downregulation of TGF-ß1/Smad2 signaling, we found that α-mangostin attenuated the expression of long non-coding RNA LincROR as well. Our results demonstrated that the effects of α-mangostin on myofibroblast activation were reverted when LincROR was overexpressed. Additionally, we showed the expression of LincROR in OSF specimens was elevated and silencing of LincROR successfully attenuated myofibroblast characteristics and TGF-ß1/Smad2 activation. Taken together, these findings indicated that the anti-fibrosis effects of α-mangostin merit consideration and may be due to the attenuation of LincROR.

PREDICTING VISUAL OUTCOME AFTER SURGERY IN PATIENTS WITH IDIOPATHIC EPIRETINAL MEMBRANE USING A NOVEL CONVOLUTIONAL NEURAL NETWORK.

PURPOSE: To develop a deep convolutional neural network that enables the prediction of postoperative visual outcomes after epiretinal membrane surgery based on preoperative optical coherence tomography images and clinical parameters to refine surgical decision making. METHODS: A total of 529 patients with idiopathic epiretinal membrane who underwent standard vitrectomy with epiretinal membrane peeling surgery by two surgeons between January 1, 2014, and June 1, 2020, were enrolled. The newly developed Heterogeneous Data Fusion Net was introduced to predict postoperative visual acuity outcomes (improvement ≥2 lines in Snellen chart) 12 months after surgery based on preoperative cross-sectional optical coherence tomography images and clinical factors, including age, sex, and preoperative visual acuity. The predictive accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network model were evaluated. RESULTS: The developed model demonstrated an overall accuracy for visual outcome prediction of 88.68% (95% CI, 79.0%-95.7%) with an area under the receiver operating characteristic curve of 97.8% (95% CI, 86.8%-98.0%), sensitivity of 87.0% (95% CI, 67.9%-95.5%), specificity of 92.9% (95% CI, 77.4%-98.0%), precision of 0.909, recall of 0.870, and F1 score of 0.889. The heatmaps identified the critical area for prediction as the ellipsoid zone of photoreceptors and the superficial retina, which was subjected to tangential traction of the proliferative membrane. CONCLUSION: The novel Heterogeneous Data Fusion Net demonstrated high accuracy in the automated prediction of visual outcomes after weighing and leveraging multiple clinical parameters, including optical coherence tomography images. This approach may be helpful in establishing personalized therapeutic strategies for epiretinal membrane management.

Is OLP potentially malignant? A clue from ZNF582 methylation.

OBJECTIVE: Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582m ) with OLP lesions, dysplastic features and squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This is a case-control study. ZNF582m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582m was evaluated only in one mucosal site of 45 normal controls. High-risk habits affecting ZNF582m such as betel nut chewing and cigarette smoking were also compared in those groups. RESULTS: OLP lesions showed significantly lower ZNF582m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high-risk habits exhibited significantly higher ZNF582m than those without high-risk habits. However, ZNF582m in OLP patients was not affected by those high-risk habits. CONCLUSIONS: OLP is unlikely to be potentially malignant based on ZNF582m levels. ZNF582m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC.

Gastric hydrodistension CT versus CT without gastric distension in preoperative TN staging of gastric carcinoma: analysis of single-center cancer registry.

Accurate staging of gastric cancer is essential for the selection and optimization of therapy. Hydrodistension of the stomach is recommended to improve the accuracy of preoperative staging with contrast-enhanced multidetector computed tomography (MDCT). This study compares the performance of contrast-enhanced gastric water distension versus a nondistension MDCT protocol for T and N staging and serosal invasion in comparison to surgical histopathology. After propensity score matching, 86 patients in each group were included for analysis. The overall accuracy of distension versus nondistension group in T staging was 45% (95% CI 35-56) and 55% (95% CI 44-65), respectively (p = 0.29). There was no difference in the sensitivity and specificity in individual T staging and assessment of serosal invasion (all p > 0.41). Individual stage concordance with pathology was not significantly different (all p > 0.41). The overall accuracy of N staging was the same for distension and nondistension groups (51% [95% CI 40-62]). The majority of N0 staging (78-81%) were correctly staged, whereas N3 staging cases (63-68%) were predominantly understaged. In summary, there was no significant difference in the diagnostic performance of individual TN staging and assessment of serosal invasion using MDCT with or without gastric water distension.

Improving the Diagnostic Performance by Adding Methylation Marker to Conventional Visual Examination in Identifying Oral Cancer.

BACKGROUND: Visual oral examination (VOE) is a conventional oral cancer screening method. This study aimed to evaluate the value of methylation marker to assist VOE in identifying oral epithelial dysplasia and oral squamous cell carcinoma (OED/OSCC) from non-cancerous lesions in a real-world situation. METHODS: 201 patients with high-risk personal habits who self-perceived oral anomaly were VOE examined, ZNF582 methylation (ZNF582m) tested, and histologically diagnosed. RESULTS: Among them, 132 patients (65.7%) were histologically diagnosed OED/OSCC. Using VOE, 56.1% OED/OSCC patients had possible oral cancer, whereas 37.7% non-OED/OSCC patients had leukoplakia. ZNF582m-positive was detected in 90.2% OED/OSCC patients and 44.9% non-OED/OSCC patients. Various logistic regression models were postulated to evaluate the diagnostic performance of conventional VOE and new strategies using ZNF582m. ROC analysis and its corresponding C-index demonstrated that either triage or co-testing models of VOE and ZNF582m could improve diagnostic performance and discriminative abilities compared with the VOE only approach. CONCLUSIONS: In conclusion, methylation marker test shows equivalent performance to an experienced judgment by oral maxillofacial surgeons and plays a significantly supplementary role in increasing the efficacy in identifying oral malignant lesions. ZNF582m may be an especially important tool for family physicians or general dentists to properly diagnose suspicious oral lesions.

miR-21 promotes the fibrotic properties in oral mucosa through targeting PDCD4.

Background/purpose: Oral submucous fibrosis (OSF) has been regarded as a premalignant disorder of oral cancer, and myofibroblasts are the main cells that are responsible for pathological fibrosis. Hence, elucidation of the molecular mechanism underlying myofibroblast activation is important to treat OSF. MicroRNA-21 (miR-21) is a well-known fibrosis non-coding RNA, and its role in the development of OSF remains largely unclear. Materials and methods: Luciferase reporter assay was used to confirm the direct interaction between miR-21 and its target programmed cell death 4 (PDCD4). The expression level of PDCD4 in OSF was examined by qRT-PCR. Myofibroblast activities were assessed by collagen gel contraction and transwell migration assays. Results: Our result validated the direct binding of miR-21 to PDCD4. We showed the expression of PDCD4 was downregulated in OSF specimens and negatively correlated with miR-21. Our results suggested that overexpression of PDCD4 in fibrotic buccal mucosal fibroblasts (fBMFs) mitigated the myofibroblast activities, including collagen gel contractility and migration capacity. Moreover, we showed miR-21 contributed to myofibroblast activation of BMFs through repression of PDCD4. Conclusion: Our results suggest that the miR-21/PDCD4 axis mediates the myofibroblast activation of BMFs, and targeting this axis may exert an anti-fibrosis effect.

Prediction of treatment outcome in neovascular age-related macular degeneration using a novel convolutional neural network.

While prognosis and risk of progression are crucial in developing precise therapeutic strategy in neovascular age-related macular degeneration (nAMD), limited predictive tools are available. We proposed a novel deep convolutional neural network that enables feature extraction through image and non-image data integration to seize imperative information and achieve highly accurate outcome prediction. The Heterogeneous Data Fusion Net (HDF-Net) was designed to predict visual acuity (VA) outcome (improvement ≥ 2 line or not) at 12th months after anti-VEGF treatment. A set of pre-treatment optical coherence tomography (OCT) image and non-image demographic features were employed as input data and the corresponding 12th-month post-treatment VA as the target data to train, validate, and test the HDF-Net. This newly designed HDF-Net demonstrated an AUC of 0.989 (95% CI 0.970-0.999), accuracy of 0.936 [95% confidence interval (CI) 0.889-0.964], sensitivity of 0.933 (95% CI 0.841-0.974), and specificity of 0.938 (95% CI 0.877-0.969). By simulating the clinical decision process with mixed pre-treatment information from raw OCT images and numeric data, HDF-Net demonstrated promising performance in predicting individualized treatment outcome. The results highlight the potential of deep learning to simultaneously process a broad range of clinical data to weigh and leverage the complete information of the patient. This novel approach is an important step toward real-world personalized therapeutic strategy for typical nAMD.

Case Report: Proteinase 3 Antineutrophil Cytoplasmic Antibody-Associated Ulcerative Colitis Presenting as Recurrent Intestinal Pseudo-Obstruction in a Teenage Patient With in situ Proteinase 3 Immunohistochemical Staining.

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with the colorectum as its major target organ. Involvement of the upper gastrointestinal tract in UC is rare and presents with nonspecific endoscopic and microscopic characteristics. Recent studies have demonstrated proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) to be a serological marker for differentiating UC from Crohn's disease in children and for detecting disease activity and nonresponse to steroid therapy and antitumor necrotizing factor-α agents. Herein, we report a 13-year-old female patient mainly presenting with recurrent bilious vomiting who was initially diagnosed with acute gastroenteritis. Intestinal pseudo-obstruction was confirmed through observation of a patent but segmentally dilated jejunum in the barium follow-through examination and other imaging; such obstruction can be attributed to backwash ileitis, superior mesenteric artery syndrome, ileus due to hypokalemia, or PR3-associated enteritis. Laboratory data revealed leukocytosis with neutrophil predominance and serum antinuclear antibody and PR3-ANCA positivity. Overlapping syndrome with autoimmune diseases was suspected. Pathology revealed a crypt abscess with aggregates of neutrophils consistent with UC but did not indicate vasculitis. The in situ immunohistochemical staining revealed PR3 density mainly in the colon and focally in the duodenum. To our knowledge, this is the first case report with in situ pathological evidence of PR3 in inflamed intestinal tissues in a patient with UC and with rare initial presentation of intestinal pseudo-obstruction-induced recurrent bilious vomiting. Whether the clinical features of the present case constitute overlap syndrome with other autoimmune disease or a disease variation of UC warrants further investigation. Notably, the patient's serum PR3-ANCA titers remained high in coincidence with increased disease activity and nonresponse to steroid therapy, but became lower after infliximab treatment. PR3-ANCA as a potential serum biomarker to aid in making differential diagnoses of UC in children, correlating disease activity, and predicting therapeutic responses was also reviewed.

The implementation of domiciliary dental care from a university hospital: A retrospective review of the patients and performed treatments in central Taiwan from 2010 to 2020.

BACKGROUND/PURPOSE: People who suffer with chronic illness, functional impairment, or cognitive impairment are not easily to visit dental clinics. Domiciliary dental care (DDC) can provide the feasible alternative for these clients. In this study, we first reported the DDC services from a university hospital in central Taiwan from 2010 to 2020. MATERIALS AND METHODS: This retrospective study collected the DDC data from Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan. The data including age, sex, geographic locations, place of residence, grade of disability, and type of dental treatment for the patients were obtained and analyzed. RESULTS: A total of 419 patients (168 females and 251 males) who received dental treatment were included in the study. The average age was 57.4 years old. The total DDC services were up to 2444 visits. The top of place of residence for DDC is patient's home (231/419; 55.13%). Scaling was the most common type of dental treatment for DDC (317/419; 75.67%). The male patients whose age <60 years old had received more DDC (p = 0.002). The profound grade of disability had higher DDC in age <60 years old group (p < 0.001). CONCLUSION: Taken together, this study demonstrates the demographic data of DDC in central Taiwan. The results may be valuable for governmental policy to improve the availability of DDC and in turn to facilitate oral health in this specific group of dental patients.

LINC00084/miR-204/ZEB1 Axis Mediates Myofibroblastic Differentiation Activity in Fibrotic Buccal Mucosa Fibroblasts: Therapeutic Target for Oral Submucous Fibrosis.

Oral submucosal fibrosis (OSF) is a precancerous condition in the oral cavity and areca nut consumption has been regarded as one of the etiologic factors implicated in the development of OSF via persistent activation of buccal mucosal fibroblasts (BMFs). It has been previously reported that an epithelial to mesenchymal transition (EMT) factor, ZEB1, mediated the areca nut-associated myofibroblast transdifferentiation. In the current study, we aimed to elucidate how areca nut affected non-coding RNAs and the subsequent myofibroblast activation via ZEB1. We found that long non-coding RNA LINC00084 was elicited in the BMFs treated with arecoline, a major alkaloid of areca nut, and silencing LINC00084 prevented the arecoline-induced activities (such as collagen gel contraction, migration, and wound healing capacities). The upregulation of LINC00084 was also observed in the OSF tissues and fibrotic BMFs (fBMFs), and positively correlated with several fibrosis factors. Moreover, we showed knockdown of LINC00084 markedly suppressed the myofibroblast features in fBMFs, including myofibroblast phenotypes and marker expression. The results from the luciferase reporter assay confirmed that LINC00084 acted as a sponge of miR-204 and miR-204 inhibited ZEB1 by directly interacting with it. Altogether, these findings suggested that the constant irritation of arecoline may result in upregulation of LINC00084 in BMFs, which increased the ZEB1 expression by sequestering miR-204 to induce myofibroblast transdifferentiation.

Inhibition of lncRNA HOTTIP ameliorated myofibroblast activities and inflammatory cytokines in oral submucous fibrosis.

BACKGROUND/PURPOSE: Long non-coding RNA HOXA transcript at the distal tip (HOTTIP) has been reported to contribute to multiple carcinomas, but whether it involves in the progression of precancerous conditions remains to be determined. Oral submucous fibrosis (OSF) has been known as an oral potentially malignant disorder and attributed to the persistent activation of the myofibroblast. METHODS: The relative expression of HOTTIP in OSF tissues has been employed by RNA-sequencing and RT-PCR analysis. HOTTIP associated myofibroblasts activities and markers in fibrotic buccal mucosal fibroblast (fBMFs) through loss of function approaches have been evaluated. RESULTS: In the present study, we found that the expression of HOTTIP was overexpressed in the OSF tissues and positively correlated with several fibrosis markers. To investigate its significance of myofibroblast activation, we first verified the expression level of HOTTIP in the patient-derived fibrotic buccal mucosal fibroblast (fBMFs) was upregulated and conducted the shRNA-mediated knockdown experiment to inhibit its expression followed by numerous examinations. We demonstrated that suppression of HOTTIP downregulated the expression of myofibroblast marker, α-SMA, and type I collagen along with the diminished myofibroblast activities (collagen gel contraction and migration capacities). Furthermore, we showed that silencing HOTTIP lessened the production of various pro-inflammatory cytokines (IL-6 and TNF-α). CONCLUSION: Collectively, our results suggest that HOTTIP plays a crucial role in the persistent activation of myofibroblasts as well as the chronic inflammation and collagen deposition.

Comparison between Totally Percutaneous Approach and Femoral Artery Cut-Down in Endovascular Aortic Repair of Ruptured Abdominal Aortic Aneurysms in a Single Hospital.

PURPOSE: To evaluate the short-term outcome of totally percutaneous endovascular aortic repair (pEVAR) of ruptured abdominal aortic aneurysms (AAAs) compared with femoral cut-down endovascular aortic repair (cEVAR). MATERIALS AND METHODS: The medical records of patients with ruptured AAAs that underwent EVAR between March 2010 and April 2017 were retrospectively reviewed. Demographic information, preoperative vital signs, preoperative laboratory data, method of anesthesia, procedure duration, aneurysm morphology, brand of device used, length of hospital stay, access complications, and short-term outcomes were recorded. Univariate as well as multivariate logistic regression was used to identify predictors of 30-day mortality. RESULTS: Among 77 patients with ruptured AAAs, 17 (22.1%) received cEVAR and 60 (77.9%) received pEVAR. Significant differences in the procedure time (P = 0.004), method of anesthesia (P = 0.040), and 30-day mortality (P = 0.037) were detected between the cEVAR and pEVAR groups. Local anesthesia plus intravenous general anesthesia (odds ratio = 0.141, P = 0.018) was an independent factor associated with 30-day mortality and local anesthesia was better than general anesthesia for 24-hr mortality (P = 0.001) and 30-day mortality (P = 0.003). CONCLUSION: In patients with ruptured AAAs, pEVAR procedures took less time than cEVAR procedures, but the length of hospital stay did not differ significantly. The 30-day mortality rate was lower with pEVAR than with cEVAR. Local anesthesia may be the key factor in EVAR to improved technical and clinical success.

Simultaneous intussusception associated with adenovirus infection in monozygotic twins: A case report.

RATIONALE: Intussusception, a common cause of intestinal obstruction in children, typically requires medical reduction. Here, we describe the case of a pair of twins who had simultaneous intussusception and were positive for fecal adenovirus-strongly indicating that adenovirus infection may be a main cause of the intussusception. PATIENT CONCERNS: Two 1-year-old twin girls were brought to Cathay General Hospital one after another on the same day. Both presented with intermittent abdominal pain, abdominal distension, diarrhea, and loss of appetite. DIAGNOSES: Their laboratory data were adenovirus positivity in rectal swab culture. Intussusception was diagnosed through a lower gastrointestinal series. INTERVENTIONS: The twins were treated with reduction for intussusception. OUTCOMES: Both patients recovered well, without recurrence. LESSONS: Most cases of intussusception are idiopathic. However, some potential risk factors-as strongly suggested by the current cases-are genetic factors and adenovirus infection.

Butylidenephthalide abrogates the myofibroblasts activation and mesenchymal transdifferentiation in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a premalignant disorder in the oral cavity, and areca nut chewing habit has been implicated in the persistent activation of myofibroblasts and the subsequent fibrosis. Therefore, it is critical to ameliorate the excessive activities of myofibroblasts prior to the malignant transformation of OSF. In the current study, we evaluated the cytotoxicity of butylidenephthalide (BP), a major phthalide ingredient of Angelica sinensis, in fibrotic buccal mucosal fibroblasts (fBMFs) as well as various myofibroblast hallmarks, including the phenotypical characteristics and fibrosis-related markers. Our results demonstrated that myofibroblast activities, including collagen gel contraction, migration, invasion and wound healing abilities were inhibited in response to BP. The expression levels of myofibroblast marker, α-smooth muscle actin (α-SMA), fibronectin and type 1 collagen A1 were decreased after exposure of BP. Moreover, we found that the EMT-related markers, Twist, Snail and ZEB1 were all downregulated after BP treatment. Most importantly, our findings demonstrated that BP impeded the binding of Snail to the E-box region in the α-SMA promoter, which may lead to inhibition of the arecoline-induced myofibroblast activities. Collectively, our data indicated that BP reduced numerous myofibroblast features in fBMFs and hindered the binding of Snail to α-SMA, thereby may function as an effective and natural antifibrosis compound.

Studies on a novel regimen for management of orofacial pain and morphine tolerance.

BACKGROUND/PURPOSE: The prevalence of orofacial pain is high but the etiology of orofacial pain is not well understood. Because of clinical treatment is not so effective, it is urgent to explore novel regimens with more effective and less side effects for clinical application. MATERIALS AND METHODS: Male mice (ICR strain) were injected with capsaicin (10µg/5 µl) in vibrissa pad. Spontaneous orofacial pain in 20 min was recorded after receiving capsaicin to quantify the nociceptive level. Green tea polyphenols (GTP 60 mg/kg), memantine (Mem 10 mg/kg), and GTPm (GTP 30 mg/kg plus Mem 3 mg/kg) were dissolved in 2% carboxymethyl cellulose, which was orally administered to mice twice per day and five times per week consecutively for 2 weeks. TruScan photobeam tracking was used to record changes of behavior and locomotor activities. RESULTS: GTPm by itself attenuated orofacial pain induced by capsaicin. Moreover, GTPm enhanced morphine analgesic effects, reduced morphine depressant side effects and delayed morphine tolerance. Along with this experiment, GTPm was tested on the hot plate (52 °C)-induced peripheral thermal pain. It was found that both memantine and GTPm reduced morphine-analgesia in hind paw thermal pain. CONCLUSION: In this study, GTP (60 mg/kg/day) orally administrated produced a significant analgesic effect on capsaicin-induced orofacial pain. Memantine combined with GTP synergistically not only reduced orofacial pain but also enhanced morphine analgesic effects. Thus, a new regimen of GTPm orally administered twice per day attenuated orofacial pain after consecutive 5 days.